1. Field of Invention
This invention relates generally to enhancing the oral bioavailability of the cytosine-based antiviral drug cidofovir.
2. Related Art
The prodrug approach has been utilized widely since the late 1950s for increasing drug bioavailability as well as drug targeting after oral administration. A prodrug is a compound that undergoes transformation within the body before eliciting a therapeutic action. This strategy is based on chemically modifying an active substance by attaching pro-moieties to pharmacophores, which ideally should overcome the biochemical and physical barriers impeding drug transport of the parent substance. Limited oral bioavailability is usually attributed to poor membrane permeability, low aqueous solubility (in the gastrointestinal fluids), or extensive first-pass metabolism.
It was long thought that intestinal absorption of most drugs proceeded by passive diffusion, in which the lipid solubility of the drug molecule was the determining factor. However, many water-soluble compounds have been shown to move well across cell membranes utilizing specialized carrier-mediated transport mechanisms. These membrane transporters play a key role in determining exposure of cells or organisms to a variety of solutes including nutrients and cellular byproducts, as well as drug molecules. Efforts have been made to improve drug bioavailability by using different pro-moieties targeting various active transportation systems present in the small intestine. Examples of transportation systems include peptide transporters, organic cation transporters, organic anion transporters, glucose transporters, vitamin transporters, bile acid transporters, fatty acid transporters, phosphate transporters, monocarboxylic acid transporters, bicarbonate transporters, ABC transporters, nucleoside transporters and amino acid transporters, as described by H.-C. Shi et al, in: R. Mannhold, H. Kubinyi, G. Folkers, Eds., Methods and Principles in Medicinal Chemistry, Wiley-VCH, Weinheim, 2003; pp. 245 287, herein incorporated by reference. All of these transporters are mainly located in the brush border membrane with variable distribution along the gastrointestinal tract, and show diverse substrate specificities.
The peptide transporter-1 (PepT1) is known to play a critical role in the absorption of diverse drugs and prodrugs from the intestinal tract. PepT1 is located in the apical enterocytic membrane of the upper small intestine where it serves as a symporter, using an electrochemical proton gradient as its driving force. Human PepT1 (hPepT1) contains 708 amino acids oriented in 12 membrane-spanning domains. The hPepT1 carrier protein is stereoselective, with peptides that contain L-amino acid residues having higher affinity for binding and transport than peptides containing one or more D-amino acids.
Many pharmaceuticals are known to utilize the intestinal PepT1 to gain entry into the systematic circulation. Such pharmaceuticals include β-lactam antibiotics such as penicillins and cephalosporins, ACE-inhibitors, renin inhibitors, thrombin inhibitors, and the dipeptide-like anti-neoplastic drug bestatin, as well as prodrugs of ganciclovir L-Dopa and pamidronate. Valacyclovir is one example of a prodrug enhancing bioavailability (3- to 5-fold) compared to the parent drug (20%), acyclovir. The increased bioavailability is suggested to result from PepT1 mediated absorption and rapid hydrolysis to acyclovir. Since PepT1 is an important di/tri peptide transporter in human enterocytes, the transportation of hundreds of different possible dipeptides, thousands of possible tripeptides, and diverse drugs and prodrugs, implies broad substrate specificity for this transporter.
Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, HPMPC] has been approved in the clinic as a treatment for AIDS-related cytomegalovirus retinitis. Cidofovir is known for its broad-spectrum activity against virtually all DNA viruses. It has been shown to have therapeutic potential not only against cytomegalovirus, but also against other herpes viruses such as herpes simplex virus (HSV), varcella-zoster virus (VZV), Epstein-Barr virus (EBV) and human herpes virus types 6, 7, and 8. It also has anti-viral activity against adenoviruses, papovaviruses such as papillomavirus and polyomavirus, pox viruses such as variola virus (the etiological agent for small pox) and other orthopox viruses such as monkeypox virus, hepadnaviruses such as hepatitis B virus, and iridiovirus.
The basic structure of cidofovir is shown in formula (I).

There is also a cyclic form of cidofovir. Cyclic cidofovir has a six-membered ring having two oxygen atoms, as shown in formula (II).

The potential use of variola virus and monkeypox virus as bioterrorism weapons has stimulated efforts to develop new drugs for treatment of smallpox and other pox infections. Cidofovir has been approved for use in the treatment of smallpox. Although, cidofovir is a very active agent against orthopoxviruses in vitro and in animal model infections; it does not show activity when administered orally due to lack of bioavailability via the oral route. Thus, cidofovir must be given systemically by injection or intravenously. Accordingly, there is a need to develop cidofovir-based drugs with enhanced oral bioavailability.